Glycolipids

As tissue-resident macrophages of the central nervous system parenchyma, microglia perform diverse essential functions during homeostasis and perturbations1. They primarily interact with neurons by means of synaptic engulfment and through the rapid elimination of apoptotic cells and non-functional synapses2. Here, by combining unbiased lipidomics and high-resolution spatial lipid imaging, deep single-cell transcriptome analysis and novel cell-type-specific mutants, we identified a previously unknown mode of microglial interaction with neurons. During homeostasis, microglia deliver the lysosomal enzyme β-hexosaminidase to neurons for the degradation of the ganglioside GM2 that is integral to maintaining cell membrane organization and function. Absence of Hexb, encoding the β subunit of β-hexosaminidase, in both mice and patients with neurodegenerative Sandhoff disease leads to a massive accumulation of GM2 derivatives in a characteristic spatiotemporal manner3. In mice, neuronal GM2 gangliosides subsequently engage the macrophage galactose-type lectin 2 receptor on microglia through N-acetylgalactosamine residues, leading to lethal neurodegeneration. Notably, replacement of microglia with peripherally derived microglia-like cells is able to break this degenerative cycle and fully restore central nervous system homeostasis. Our results reveal a mode of bidirectional microglia-neuron communication centred around GM2 ganglioside turnover, identify a microgliopathy and offer therapeutic avenues for these maladies.

Ceramides are bioactive lipids that play a crucial role in cellular signaling and structural integrity (Nat Rev Mol Cell Biol 19:175-191, 2018). As members of the sphingolipid family, ceramides consist of a sphingoid base attached to a fatty acid (Annu Rev Biophys 47:633-654, 2018). Their unique structure confers both hydrophobic and amphipathic properties, enabling them to organize into membrane microdomains that influence cellular dynamics (Annu Rev Biophys 47:633-654, 2018). In recent years, ceramides have garnered attention for their role in modulating a range of cellular and organismal functions. Unlike other lipids that primarily serve structural roles, ceramides act as bioactive lipids in key signaling pathways, mediating stress responses such as inflammation, oxidative stress, growth inhibition, metabolism, autophagy, and apoptosis (J Lipid Res 60:913-918, 2019). Their regulatory effects are particularly important in immune cells, where ceramides can influence cell fate, modulate cellular metabolism, affect cytokine production, and dictate responses to external stimuli (Nature 510:58-67, 2014). Since ceramides maintain a dynamic equilibrium with other sphingolipids within a cell, understanding their role in immune cells in isolation provides only a partial perspective. Nevertheless, as a bioactive lipid and the central precursor of other sphingolipids, ceramides play a pivotal role in immune cells, deserving focused attention.

In this single-arm, non-randomized, phase 2 trial (NCT03363373), 74 patients with relapsed/refractory high-risk neuroblastoma and residual disease in bone/bone marrow (BM) received naxitamab on Days 1, 3, and 5 (3 mg/kg/day) with granulocyte-macrophage colony-stimulating factor (Days -4 to 5) every 4 weeks, until complete response (CR) or partial response (PR) followed by 5 additional cycles every 4 weeks. Primary endpoint in the prespecified interim analysis was overall response (2017 International Neuroblastoma Response Criteria). Among 26 responders (CR + PR) in the efficacy population (N = 52), 58% had refractory disease, and 42% had relapsed disease. Overall response rate (ORR) was 50% (95% CI: 36-64%), and CR and PR were observed in 38% and 12%, respectively. With the 95% CI lower limit for ORR exceeding 20%, the primary endpoint of overall response was met. Patients with evaluable bone disease had a 58% (29/50) bone compartment response (CR, 40%; PR, 18%). BM compartment response was 74% (17/23; CR, 74%). One-year overall survival and progression-free survival (secondary endpoints) were 93% (95% CI: 80-98%) and 35% (95% CI: 16-54%), respectively. Naxitamab-related Grade 3 adverse events included hypotension (58%) and pain (54%). Overall, naxitamab demonstrated clinically meaningful efficacy with manageable safety in patients with residual neuroblastoma in bone/BM.

The glycosylphosphatidylinositol (GPI) biosynthesis pathway is critical for antifungal drug development. As a key component of this pathway, GPI transamidase (GPIT) catalyzes the attachment of GPI anchors to proteins, a process essential for fungal cell wall integrity and virulence. Despite its biological significance, structural and mechanistic insights into fungal GPIT remain limited. Here, a series of cryo-electron microscopy structures capturing distinct functional states of Saccharomyces cerevisiae GPIT is reported, including GPIT complexed with a GPI anchor, GPIT bound to a substrate-mimetic peptide, and an unprecedented dimeric GPIT assembly. These structures reveal the conserved GPI anchor binding site formed by Gab1 and Gpi16, as well as a key protein substrate recognition site, Gpi16 Y550. Comparative structural analyses uncover fungal-specific adaptations and the dynamic accommodation of catalytic subunit Gpi8. The dimeric GPIT structure exhibits a unique T-shaped organization unexpectedly mediated by transmembrane helices of Gab1 and Gaa1, a configuration unlikely to form in the human counterpart. This study provides a molecular framework for understanding GPIT function and species-specific divergences, providing a molecular basis for antifungal drug development.